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Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Daniel Barnes 1 Matti Rookus 2 Lesley Mcguffog 1 Goska Leslie 1 Thea Mooij 2 Joe Dennis 1 Nasim Mavaddat 1 Julian Adlard 3 Munaza Ahmed 4 Kristiina Aittomäki 5 Nadine Andrieu 6, 7, 8, 9 Irene Andrulis 10, 11 Norbert Arnold 12 Banu Arun 13 Jacopo Azzollini 14 Judith Balmaña 15, 16 Rosa Barkardottir 17, 18 Daniel Barrowdale 1 Javier Benitez 19, 20 Pascaline Berthet 21 Katarzyna Białkowska 22 Amie Blanco 23 Marinus Blok 24 Bernardo Bonanni 25 Susanne Boonen 26 Åke Borg 27 Aniko Bozsik 28 Angela Bradbury 29 Paul Brennan 30 Carole Brewer 31 Joan Brunet 32 Saundra Buys 33 Trinidad Caldés 34 Maria Caligo 35 Ian Campbell 36, 37 Lise Lotte Christensen 38 Wendy Chung 39 Kathleen Claes 40 Chrystelle Colas 7 Marie-Agnès Collonge-Rame 41 Jackie Cook 42 Mary Daly 43 Rosemarie Davidson 44 Miguel de la Hoya 34 Robin de Putter 40 Capucine Delnatte 45 Peter Devilee 46 Orland Diez 15, 16 Yuan Chun Ding 47 Susan Domchek 48 Cecilia Dorfling 49 Martine Dumont 50 Ros Eeles 51 Bent Ejlertsen 52 Christoph Engel 53 D Gareth Evans 54, 55 Laurence Faivre 56, 57 Lenka Foretova 58 Florentia Fostira 59 Michael Friedlander 60 Eitan Friedman 61, 62 Debra Frost 1 Patricia Ganz 63 Judy Garber 64 Andrea Gehrig 65 Anne-Marie Gerdes 66 Paul Gesta 67 Sophie Giraud 68 Gord Glendon 10 Andrew Godwin 69 David Goldgar 33 Anna González-Neira 20 Mark Greene 70 Daphne Gschwantler-Kaulich 71 Eric Hahnen 72 Ute Hamann 73 Helen Hanson 74 Julia Hentschel 75 Frans Hogervorst 2 Maartje Hooning 76 Judit Horvath 77 Chunling Hu 78 Peter Hulick 79, 80 Evgeny Imyanitov 81 Claudine Isaacs 82 Louise Izatt 83 Angel Izquierdo 32 Anna Jakubowska 22 Paul James 37, 84 Ramunas Janavicius 85, 86 Esther John 87 Vijai Joseph 88 Beth Karlan 23, 89 Karin Kast 90 Marco Koudijs 91 Torben Kruse 92 Ava Kwong 93, 94, 95 Yael Laitman 61 Christine Lasset 96, 97 Conxi Lazaro 32 Jenny Lester 98, 89 Fabienne Lesueur 6, 7, 9, 99 Annelie Liljegren 100 Jennifer Loud 70 Jan Lubiński 22 Phuong Mai 101 Siranoush Manoukian 14 Véronique Mari 102 Noura Mebirouk 6, 7, 99, 9 Hanne Meijers-Heijboer 103 Alfons Meindl 104 Arjen Mensenkamp 105 Austin Miller 106 Marco Montagna 107 Emmanuelle Mouret-Fourme 7 Semanti Mukherjee 88 Anna Marie Mulligan 108, 109 Katherine Nathanson 110 Susan Neuhausen 47 Heli Nevanlinna 5 Dieter Niederacher 111 Finn Cilius Nielsen 52 Liene Nikitina-Zake 112 Catherine Nogues 113, 114 Edith Olah 28 Olufunmilayo Olopade 115 Kai-Ren Ong 116 Aoife O'Shaughnessy-Kirwan 117 Ana Osorio 19, 20 Claus-Eric Ott 118 Laura Papi 119 Sue Park 120, 121 Michael Parsons 122 Inge Sokilde Pedersen 123 Bernard Peissel 124 Ana Peixoto 125 Paolo Peterlongo 126 Georg Pfeiler 71 Kelly-Anne Phillips 127, 37 Karolina Prajzendanc 22 Miquel Angel Pujana 128 Paolo Radice 124 Juliane Ramser 129 Susan Ramus 130, 131 Johanna Rantala 100 Gad Rennert 132 Harvey Risch 133 Mark Robson 88 Karina Rønlund 134 Ritu Salani 135 Hélène Schuster 136, 137, 138 Leigha Senter 135 Payal Shah 48 Priyanka Sharma 139 Lucy Side 140 Christian Singer 71 Thomas Slavin 141 Penny Soucy 50 Melissa Southey 142, 37, 143 Amanda Spurdle 122 Doris Steinemann 144 Zoe Steinsnyder 88 Dominique Stoppa-Lyonnet 7, 145, 146 Christian Sutter 147 Yen Yen Tan 71 Manuel Teixeira 125, 148 Soo Hwang Teo 149, 150 Darcy Thull 101 Marc Tischkowitz 151, 1 Silvia Tognazzo 107 Amanda Toland 135 Alison Trainer 127, 37 Nadine Tung 152 Klaartje van Engelen 103 Elizabeth van Rensburg 49 Ana Vega 19, 153, 154 Jeroen Vierstraete 155 Gabriel Wagner 71 Lisa Walker 156 Shan Wang-Gohrke 157 Barbara Wappenschmidt 158 Jeffrey Weitzel 141 Siddhartha Yadav 159 Xin Yang 1 Drakoulis Yannoukakos 59 Dario Zimbalatti 124 Kenneth Offit 88 Mads Thomassen 92 Fergus Couch 159 Rita Schmutzler 158 Jacques Simard 50 Douglas Easton 1 Georgia Chenevix-Trench 122 Antonis Antoniou 1
1 CAM - University of Cambridge [UK]
2 NKI - Netherlands Cancer Institute
3 Chapel Allerton Hospital
4 GOSH - Great Ormond Street Hospital for Children [London]
5 University of Helsinki
6 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
7 Institut Curie [Paris]
8 MINES ParisTech - École nationale supérieure des mines de Paris
9 PSL - Université Paris sciences et lettres
10 MSH - Mount Sinai Hospital [Toronto, Canada]
11 University of Toronto - University of Toronto
12 Christian-Albrechts University of Kiel
13 The University of Texas M.D. Anderson Cancer Center [Houston]
14 Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan]
15 VHIO - Vall d'Hebron Institute of Oncology [Barcelone]
16 Vall d'Hebron University Hospital [Barcelona]
17 Landspitali National University Hospital of Iceland
18 University of Iceland [Reykjavik]
19 CIBER de Enfermedades Raras (CIBERER)
20 CNIO - Spanish National Cancer Research Center
21 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
22 Pomeranian Medical University
23 University of California
24 MUMC - Maastricht University Medical Centre
25 EIO - European Institute of Oncology IRCCS [Milan, Italy]
26 Zealand University Hospital [Roskilde, Denmark]
27 Lund University [Lund]
28 National Institute of Oncology [Budapest, Hungary]
29 Abramson Cancer Center [philadelphia]
30 Institute of Genetic Medicine [Newcastle]
31 Royal Devon & Exeter Hospital, Exeter, UK
32 Catalan Institute of Oncology [Barcelone, Espagne]
33 Huntsman Cancer Institute [Salt Lake City]
34 IdISSC - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain]
35 Pisa University Hospital
36 Peter MacCallum Cancer Centre [Melbourne, Australie]
37 University of Melbourne
38 Aarhus University Hospital
39 Columbia University [New York]
40 Ghent University Hospital
41 CHU Besançon - Centre Hospitalier Universitaire de Besançon
42 Sheffield Children's NHS Foundation Trust
43 Fox Chase Cancer Center
44 Queen Elizabeth University Hospital (Glasgow)
45 CHU Nantes - Centre hospitalier universitaire de Nantes
46 Leiden University Medical Center (LUMC)
47 Beckman Research Institute of the City of Hope
48 Abramson Cancer Center
49 University of Pretoria [South Africa]
50 Centre Hospitalier Universitaire de Québec Research Center [Canada]
51 Royal Marsden NHS Foundation Trust
52 Copenhagen University Hospital
53 University of Leipzig [Leipzig, Allemagne]
54 University of Manchester [Manchester]
55 MAHSC - Manchester Academic Health Science Centre
56 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
57 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
58 RECAMO - Masaryk Memorial Cancer Institute
59 INRASTES - Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety
60 NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie]
61 Chaim Sheba Medical Center
62 Tel Aviv University [Tel Aviv]
63 Jonsson Comprehensive Cancer Center
64 Dana-Farber Cancer Institute [Boston]
65 University of Würzburg
66 Rigshospitalet [Copenhagen]
67 CH Georges Renon Niort - Centre Hospitalier Georges Renon [Niort]
68 HCL - Hospices Civils de Lyon
69 University of Kansas [Kansas City]
70 NCI-NIH - National Cancer Institute [Bethesda]
71 Medizinische Universität Wien = Medical University of Vienna
72 University of Cologne
73 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
74 Lancashire NHS Foundation Trust
75 University Hospital Leipzig
76 Department of Medical Oncology, Family Cancer Clinic
77 University of Münster
78 Mayo Clinic
79 NorthShore University HealthSystem [Evanston, IL, USA]
80 The University of Chicago Medicine [Chicago]
81 N. N. Petrov Institute of Oncology
82 Georgetown Lombardi Comprehensive Cancer Center
83 Guy's and St Thomas' NHS Foundation Trust [London, UK]
84 Peter MacCallum Cancer Center, East Melbourne
85 Vilnius University [Vilnius]
86 The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania
87 Stanford University School of Medicine [CA, USA]
88 Memorial Sloane Kettering Cancer Center [New York]
89 Cedars-Sinai Medical Center
90 TU Dresden - Technische Universität Dresden = Dresden University of Technology
91 University Medical Center [Utrecht]
92 Odense University Hospital [Odense, Denmark]
93 The Hong Kong Hereditary Breast Cancer Family Registry
94 HKU - The University of Hong Kong
95 HKSH - Hong Kong Sanatorium and Hospital [Hong Kong]
96 Equipe de prévention et épidémiologie génétique
97 LBBE - Laboratoire de Biométrie et Biologie Evolutive - UMR 5558
98 David Geffen School of Medicine [Los Angeles]
99 Fondation MINES ParisTech
100 Karolinska Institutet [Stockholm]
101 University of Pittsburgh School of Medicine
102 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
103 Amsterdam UMC
104 TUM - Technical University of Munich
105 Radboud University Medical Center [Nijmegen]
106 Roswell Park Cancer Institute [Buffalo]
107 Veneto Institute of Oncology IOV-IRCCS [Padua, Italy]
108 University of Toronto
109 University Health Network
110 University of Pennsylvania [Philadelphia]
111 University Hospital Düsseldorf
112 Latvian Biomedical Research and Study Centre [Rīga]
113 SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale
114 Institut Paoli-Calmettes
115 University of Chicago
116 Birmingham Women's and Children's NHS Foundation Trust
117 CUH - Cambridge University Hospitals - NHS
118 Charité Campus Virchow-Klinikum (CVK)
119 Università degli Studi di Firenze = University of Florence [Firenze]
120 SNUCM - Seoul National University College of Medicine [Séoul, Corée du Sud]
121 SNU - Seoul National University [Seoul]
122 QIMR Berghofer Medical Research Institute
123 AAU - Aalborg University [Denmark]
124 IRCCS Istituto Nazionale dei Tumori [Milano]
125 IPO Porto - Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto
126 IFOM - IFOM, Istituto FIRC di Oncologia Molecolare
127 Peter MacCallum Cancer Center
128 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge [Barcelone]
129 Klinikum rechts der Isar [Munich, Germany]
130 UNSW - University of New South Wales [Sydney]
131 Garvan Institute of Medical Research [Sydney, Australia]
132 Technion Faculty of Medicine [Haifa, Israel]
133 Yale University School of Medicine
134 Vejle Hospital
135 OSU - Ohio State University [Columbus]
136 Centre de lutte contre le cancer Paul-Strauss
137 ICANS - Institut de Cancérologie de Strasbourg Europe
138 Immuno-Rhumatologie Moléculaire
139 University of Kansas Medical Center [Lawrence]
140 Princess Anne Hospital
141 City of Hope Comprehensive Cancer Center [Duarte]
142 Monash University [Clayton]
143 Cancer Council Victoria [Melbourne, VIC, Australia]
144 MHH - Hannover Medical School [Hannover]
145 U830 - Unité de génétique et biologie des cancers
146 Université Paris Descartes (Paris 5)
147 Heidelberg University Hospital [Heidelberg]
148 Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal]
149 Malaysia and University Malaya Cancer Research Institute
150 Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie]
151 McGill University = Université McGill [Montréal, Canada]
152 BIDMC - Beth Israel Deaconess Medical Center [Boston]
153 Grupo de Medicina Xenómica - Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain]
154 Instituto de Investigaciones Sanitarias
155 UGENT - Ghent University [Belgium]
156 Oxford University Hospitals NHS Trust
157 Universitätsklinikum Ulm - University Hospital of Ulm
158 University Hospital of Cologne [Cologne]
159 Mayo Clinic [Rochester]
Abstract : We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 −72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10 −50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10 −22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10 −12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Keywords : BRCA1/2 breast cancer ovarian cancer PRS genetics
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Journal articles
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https://www.hal.inserm.fr/inserm-03193473
Contributor : Christine Dupuis <>
Submitted on : Thursday, April 8, 2021 - 7:20:35 PM
Last modification on : Wednesday, September 8, 2021 - 5:32:10 PM

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INSERM | HCL | CGFL | BACLESSE | CURIE | PAOLI_CALMETTES | PSL | FNCLCC | BIOENVIS | UNIV-LYON1 | ENSMP | UNIV-COTEDAZUR | UNIV-AMU | U1252 | ENSMP_CBIO | CNRS | UDL | SITE-ALSACE | COMUE-NORMANDIE | IRD | INRIA | INSTITUT-TELECOM | PARISTECH | UNIV-PARIS

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Daniel Barnes, Matti Rookus, Lesley Mcguffog, Goska Leslie, Thea Mooij, et al.. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genetics in Medicine, Nature Publishing Group, 2020, 22 (10), pp.1653-1666. ⟨10.1038/s41436-020-0862-x⟩. ⟨inserm-03193473⟩

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